Overview

This study is designed to assess the antitumor activity of combination therapy of SMT-NK (allogeneic natural killer cells) and pembrolizumab versus pembrolizumab monotherapy in patients with advanced biliary tract cancer

Eligibility

Inclusion Criteria:

1. Patients who received a histopathological or cytologic diagnosis of nonresectable, advanced biliary tract carcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer) and patients with refractory disease after chemotherapy and/or patients who have difficulty with chemotherapy due to side effects of chemotherapy.
2. Patients who receives an explanation from the trial manager about the purpose, contents, and characteristics of the Investigational products for the clinical trial and is signed by the person, guardian or legal representative in the written informed consent.
3. 19 to 80 years old on day of signing informed consent.
4. Histopathological or cytologic diagnosis of advanced adenocarcinoma of the biliary tract and those with measurable lesions for RECIST evaluation
   • Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of 10mm by CT scan
   • Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan
5. Have a performance status of ≤2 on the ECOG Performance Scale.
6. Patients who survival period is expected to be at least 3 months.
7. Demonstrate laboratory test results the following conditions:
   • ANC (Absolute Neutrophil Count) ≥ 1,500/μL
   • Hemoglobin≥ 9 g/dL
   • Platelet> 80,000/μL
   • serum BUN & Creatinine ≤ 2.0 x upper limit of normal (ULN)
   • AST & ALT ≤ 5.0 x upper limit of normal (ULN)
   • Bilirubin ≤ 5mg/dL
   • Albumin ≥ 2.8g/dL
   • Prothrombin time (PT)% activity ≥ 70%
8. Patients or partners who has agreed to the appropriate use of contraceptives by two or

   more during the treatment period (including Survival follow-up period) (for men, those who have agreed not to provide sperm)

9. Patients who meet one or more of the following conditions:
   • Patients have at least 1% Combined Positive Score (CPS) PD-L1 expression detected on the tumor, as determined by *immunohistochemistry performed by a central laboratory.
     • CPS = (number of PD-L1 positive tumor cells, lymphocytes, macrophage)/ (total number of viable tumor cells) X 100
     • Immunohistochemistry: IHC 22C3 pharmDx test

       ② Patients who have a positive MSI-H or dMMR test

       • MSI-high positive tumors analyzed by PCR
       • dMMR positive tumors analyzed by immunohistochemical staining
     • MSI-H was measured by PCR, and positive finding when two or more unstable

       markers were detected in PCR for 5 microsatellite markers, **dMMR is analyzed by immunohistochemical staining and positive when the discovery of one or more genes in MLH1, MSH2, MSH6 and PMS2 staining is lost.

Exclusion Criteria:

1. Patients who have previous history
   • Immune deficiency or autoimmune disease that can be aggravated by immunotherapy (for example: Rheumatoid arthritis, systemic lupus erythematosus, vasculitis, multiple sclerosis, Crohn's disease, ulcerative colitis, adolescent-developed insulin-dependent diabetes mellitus).
   • Immune deficiency disease
   • Pneumonia, colitis, hepatitis, nephritis, endocrine diseases associated with immunodeficiency (hypophysis, thyroid dysfunction, Type 1 diabetes, etc.)
   • Obvious myocardial failure or uncontrolled arterial hypertension
   • Active central nervous system (CNS) metastases and/or carcinomatous meningitis.
   • Non-infectious pneumonia, interstitial lung disease
   • Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
   • Hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] is detected) infection or active tuberculosis
   • Active infection (if systemic treatment is required)
2. Has a diagnosed and/or treated additional malignancy within 5 years prior to signing

   informed consent except for curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin

3. Has a previous history of anti-angiogenic agent treatment before signing informed consent
4. Has a known serious allergic history
5. Has a known serious mental illness
6. Identified the following in Screening:
   • CRP ≥10 mg/dl and albumin ≤3.0 g/dl are suspected of cancer cachexia
   • Patients who have symptomatic ascites that is not controlled by medical treatment
7. Has received chemotherapy not less than 4 weeks old before randomization
8. Has received a live vaccine within 4 weeks before randomization
9. Is currently participating in or has participated in another clinical study within 4 weeks before randomization or the adverse event due to investigational drug administered remain before randomization
10. Has previously administrated Pembrolizumab and another anti-PD-1/PD-L1 agent
11. Has previously administrated immune-cell therapy (including natural killer cell etc.)
12. Female who are pregnant, breastfeeding or intending to become pregnant during the study period.
13. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab
14. Has performed major surgery within 4 weeks prior to signing informed consent
15. Patients who are unsuitable to participate in clinical trials by investigator's decision